The success of a prophylactic vaccine against HIV infection depends upon its ability to elicit a potent and long-lived immune response. Recent studies in murine models have shown that systemic viral infections, that cause acute infection, induce a robust primary and memory immune response. This highlights the urgency for exploring the mechanisms by which live infections induce efficient immune responses and for applying this principle to HIV vaccination strategies. The major differences between live infections and subunit vaccines include high antigenic load and the possibility of low-level antigenic persistence. Another major difference is that live infections induce a potent innate response, where as sub-unit vaccines do not. Now there is growing evidence that the innate immune responses may shape the downstream events of adaptive immune response. We started exploring the innate reactions elicited by live infections and examine how these events affect the generation of adaptive response. We found that type-I interferons, induced early after infection, play an unexpected role in both modulating the early innate responses as well as enhancing the immunogenicity of the vaccine. We hypothesize that similar rules may also govern the generation of immune response against HIV vaccines. The overall goal of this effort is to derive ways to enhance primary and memory responses against HIV vaccines, and at the same time gaining new insights into innate determinants that enhance immunogenicity which could also provide guide lines for other HIV vaccine approaches. This proposal is aimed at exploiting the role of type-I interferons in enhancing immune memory against candidate HIV/SIV vaccines and explores the possibility of translating our knowledge gained through rodent models into rhesus macaque models. Specifically we propose to explore the feasibility of incorporating type-I interferon (IFN alpha/beta) producing DNA constructs as genetic adjuvants for enhancing immunogenicity of HIV/SIV vaccines. The approach will first be optimized in murine models and then be tested in macaques. The magnitude, breadth, duration and protective ability of immune responses against HIV/SIV vaccines will be quantitated using newly available high-resolution immunological methods such as MHC tetramer binding and single cell cytokine assays.